Efficacy and Safety of the Ophthalmic Solution PRO-087 Versus Systane ® Ultra and Ultra Preservative Free (087LATAMFIV)

Design Controlled, double-blind, randomized, clinical trial comparing the safety and efficacy parameters between a group of subjects with a diagnose of mild to moderate tear film dysfunction syndrome under a regimen of ophthalmic solution lubricant drops PRO-087 versus subject under Systane® Ultra or Systane® Ultra preservative free, with the same diagnosis, with a follow-up of 90 days

MAIN OBJECTIVE:

To evaluate the effectiveness of preservative-free ophthalmic formulation PRO-087 (by Laboratorios Sophia, S.A. de C.V.) to restore the anatomical and physiological characteristics of the ocular surface, as well as its distribution and the characteristics of the mild to moderate tear film dysfunction syndrome compared to Systane ® Ultra and Ultra Systane ® preservative free (by Laboratorios Alcon, S.A. de C.V.).

SPECIFIC OBJECTIVES:

To evaluate the safety of the preservative-free ophthalmic formulation PRO-087 (by Laboratorios Sophia, S.A. de C.V.) on the corneal and conjunctival epithelium, intraocular pressure, and structures of anterior and posterior segment in patients with tear film dysfunction syndrome from mild to moderate.

To determine the correlation between improvement of clinical status and perceived improvement of symptoms of each participant in each study group.

To compare the qualitative and quantitative histological status of the ocular surface before and after the pharmacological intervention in each study group to determine the evolution under the intervention of PRO-087.

To evaluate the quantitative rating of tear film production by the Schirmer Test throughout the study.

To qualitatively assess the tear film production by measuring the tear film break-up time stained with fluorescein and cobalt filter.

Blinding:

The double-blind study is a procedure in which the patient and the treating doctor ignore to which intervention group the study patient was assigned. To achieve the blinding of both the drug in research and both comparator drugs, these will be labeled in the same way (masking). Besides the figure of an unblinded pharmacist, who is responsible for the delivery of the medication to the patient, will be added. Blinding codes are protected by an outsider appointed by the study sponsor. The codes are also available in the research center (fully sealed), so that they can be consulted by the investigator in case a subject presents a serious adverse event, prior authorization from the study sponsor; the blinding also continues rigorous during the data analysis and interpretation.

patients with tear film dysfunction, classified as mild to moderate, will be included and randomized into 3 groups; the first being treated with PRO-087 ophthalmic solution, the second with Systane® Ultra ophthalmic solution, and the third with ophthalmic solution Systane® Ultra preservative free.

Pharmacological Intervention

The pharmacological intervention will be the instillation of the ophthalmic solution in the bottom of the conjunctival sac during the waking period, in any of the following study groups:

1. Preservative free PRO-087 ophthalmic solution. Dropper bottle. Multidose 1 drop every 4 hours for 90 days.
2. Systane® Ultra ophthalmic solution. Dropper bottle. Multidose. 1 drop every 4 hours for 90 days.
3. Systane ® Ultra preservative free ophthalmic solution. Single-use vials. 1 drop every 4 hours for 90 days.

• PRO-087 (Drug), also known as Chondroitin sulfate, sodium hyaluronate: 0.1% sodium hyaluronate, free-preservative 0.18% chondroitin sulphate
• Systane Ultra (Drug), also known as polyethylene glycol 400, propylene glycol: Is a sterile solution containing polyethylene glycol 400, propylene glycol, hydroxypropyl-guar, sorbitol, aminomethylpropanol, boric acid, potassium chloride, sodium chloride and POLYQUAD® (poly-hydronium chloride) 0.001% as preservative.
• Systane Ultra Preservative Free (Drug), also known as Polyethylene Glycol 400 0.4%, Propylene Glycol 0.3%: Polyethylene Glycol 400 0.4%Lubricant, Propylene Glycol 0.3% Lubricant,

Primary outcomes

• Visual Acuity [Change from Baseline visual acuity at 90 days]: Best-corrected visual acuity

Secondary outcomes

• Corneal Epithelization Defects With Rose of Bengal [Final Visit (day 90)]: Percentage of the damaged epithelium of the ocular surface, reduction of staining according to the oxford scale.
• Tear Film Break-up Time (TBUT) [Base line and Final Visit (day 90)]: Tear breakup time (TBUT) is a clinical test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is observed under a broad beam of cobalt blue illumination. The TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film, as seen in this progression of these slit lamps photos over time. A TBUT under 10 seconds is considered abnormal
• Schirmer Test [Base line and Final Visit (day 90)]: Schirmer's test determines whether the eye produces enough tears to keep it moist. This test is used when a person experiences very dry eyes or excessive watering of the eyes. It poses no risk to the subject. A negative (more than 10 mm of moisture on the filter paper in 5 minutes) test result is normal. Both eyes normally secrete the same amount of tears.
• Adverse Events [90 days]: Presence of adverse events modifying some of the abovementioned criteria or others, evaluated as serious.
• Ocular Surface Disease Index (OSDI) [Change from Baseline OSDI at 90 days]: The OSDI, which was created to order to quickly assess the symptoms of ocular irritation in dry eye disease and how they affect functioning related to vision. This 12-item questionnaire assesses dry eye symptoms and the effects it has on vision-related function in the past of the patient's life. The questionnaire has 3 subscales: ocular symptoms, vision-related function, and environmental triggers. Patients rate their responses on a 0 to 4 scale with 0 corresponding to "none of the time" and 4 corresponding to "all of the time." A final score is calculated which ranges from 0 to 100 with scores 0 to 12 representing normal, 13 to 22 representing mild dry eye disease, 23 to 32 representing moderate dry eye disease, and greater than 33 representing severe dry eye disease.
• Goblet Cells Population [Change from Baseline Goblet cells population at 90 days]: Increase of 20% from baseline
• Corneal Epithelization Defects With Fluorescein [Final Visit (day 90)]: Percentage of the damaged epithelium of the ocular surface, reduction of staining according to the oxford scale.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* >18 to < 90 years old
* Both sexes
* Mild to moderate tear film dysfunction clinical diagnose
* Mild to moderate clinical stage of the disease

  * TBUT > 5 sec. and < 10 sec.
  * Schirmer: > 4 mm and < 14 mm
  * OSDI < 30 points
  * Corneal staining < grade III on the Oxford scale
* Availability to go to each revision when indicated.

Exclusion Criteria:

General Criteria

1. Subjects with topical and/or systemic medication or mechanical devices that interfere determinedly on the results of the study (such as topical immunomodulators, punctal plugs, corticosteroids, preservative artificial tears, contact lenses).
2. Subjects (females) with active sexual life that do not use a contraceptive method.
3. Female subjects who are pregnant or lactating
4. Female subjects with a positive urine pregnancy test
5. Positive drug addictions* (verbal interrogatory)
6. Subjects who have participated on any other research clinical trials on the last 40 days
7. Subjects legal or mentally disabled to give an informed consent for participating on this study
8. Subjects who can't comply with the appointments or with every protocol requirement.

Criteria related with ophthalmic ailments

1. Serious tear film dysfunction syndrome TBUT < 5 s Schirmer: < 4 mm OSDI > 30 pints Corneal staining > grade III on the Oxford scale
2. Non perforated corneal ulcer
3. Perforated corneal ulcer
4. Autoimmune corneal ulcer
5. Ocular surface scarring diseases
6. Ocular surface or annexes metaplastic lesions
7. Fibro vascular proliferation lesions on the conjunctival and/or corneal surface (i.e.: pterygium)
8. Concomitant chronic inflammatory diseases on any ocular structure
9. Acute or infectious inflammatory disease
10. Corneal disease potentially requiring a treatment during the following 3 months
11. Use of topical or systemic drug products classified as forbidden
12. Ocular surgical procedures 3 months before the protocol inclusion
13. Treatments or procedures indicated on the tear film dysfunction treatment, as punctal silicone plugs.
14. Posterior segment diseases requiring a treatment or threatening the visual prognosis
15. Retinal diseases potentially requiring treatment during the following 3 months
16. History of penetrating keratoplasty.
17. Soft or hard contact lenses use during the last month from inclusion day

Participant flow

Outcome results

• Visual Acuity (Primary), Mean, LogMAR: PRO-087 PF 0.187 +/- 0.25; Systane Ultra 0.215 +/- 0.26; Systane Ultra PF 0.219 +/- 0.23 (p 0.080)
• Corneal Epithelization Defects With Rose of Bengal (Secondary), Number, percentage of defects: PRO-087 PF 80.6; Systane Ultra 73.4; Systane Ultra PF 77.8 (p 0.468)
• Tear Film Break-up Time (TBUT) (Secondary), Mean, seconds: PRO-087 PF 7.08 +/- 1.01; Systane Ultra 7.10 +/- 1.01; Systane Ultra PF 7.10 +/- 1.01 (p 0.0001)
• Schirmer Test (Secondary), Mean, mm: PRO-087 PF 9.48 +/- 2.5; Systane Ultra 9.05 +/- 2.7; Systane Ultra PF 9.25 +/- 2.7 (p 0.003)
• Adverse Events (Secondary), Number, percentage of adverse events: PRO-087 PF 19.2; Systane Ultra 21.1; Systane Ultra PF 20.6 (p 0.930)
• Ocular Surface Disease Index (OSDI) (Secondary), Mean, score on a scale: PRO-087 PF 16.59 +/- 7.3; Systane Ultra 15.74 +/- 7.0; Systane Ultra PF 16.31 +/- 7.7 (p 0.548)
• Goblet Cells Population (Secondary), Mean, cells/mm^2: PRO-087 PF 341.2 +/- 136.9; Systane Ultra 338.5 +/- 150.6; Systane Ultra PF 327.4 +/- 146.8 (p 0.170)
• Corneal Epithelization Defects With Fluorescein (Secondary), Number, percentage of defects: PRO-087 PF 52.8; Systane Ultra 53.1; Systane Ultra PF 53.7 (p 0.085)

Adverse events

Time frame: Adverse events were monitored and recorded throughout the study, an average of 2 years, since october 2016 to october 2018.

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2016-02-01)

• Leopoldo Baiza, MD, Study director, Laboratorios Sophia S.A de C.V.